Virtual Screening of Dihydropyrimidinone and Chromene Derivatives for Potential Dual Inhibition of SARS-CoV-2 Proteases Mpro and PLpro

The novel coronavirus SARS-CoV-2, responsible for the global COVID-19 pandemic, was first identified in Wuhan, China, in December 2019. Despite extensive research, an effective treatment remains elusive, with most existing therapies involving repurposed drugs. Key targets for antiviral drug development include the viral protease enzymes Main Protease (Mpro) and Papain-Like Protease (PLPro), both critical for viral replication and immune evasion. Mpro contains a catalytic dyad (His41, Cys145), while PLPro features a catalytic triad (Cys111, His273, Asp287), both essential for the virus's lifecycle. Chromene and Dihydropyrimidinone (DHPM) compounds, known for their diverse biological activities, have not been fully explored as potential treatments for SARS-CoV-2. Previous research as preliminary study identified four compounds that passed cytotoxicity tests and antiviral bioassays against SARS-CoV-2, with IC50 values ranging from 6.187µM to 25.21µM. Based on these findings, the current research aims to design new derivatives of DHPM and chromene compounds by introducing 14 functional groups to the aromatic rings of these lead compounds. As a result, a database of 838 new derivatives was generated. These derivatives were then analyzed through computational screening and molecular docking studies to evaluate their binding interactions with the viral protease targets. The screening process employed a selection score (SS) system based on ADMET properties and docking scores, allowing for the identification of the most promising candidates in comparison to reference drugs. Three compounds were identified with higher SS values: (R)-2-amino-4-(2,4-diethoxy-5-methylphenyl)-7-hydroxy-4H-chromene-3-carbonitrile, (R)-2-amino-4-(2,4-diethoxy-5-fluorophenyl)-7-hydroxy-4H-chromene-3-carbonitrile, and (R)-2-amino-4-(5-(dimethylamino)-2,4-diethoxyphenyl)-7-hydroxy-4H-chromene-3-carbonitrile. These compounds are considered promising candidates for further development as potential anti-SARS-CoV-2 drugs due to their favorable pharmacokinetic profiles and docking results.